Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer

Marialuisa Sponziello, Silvia Benvenuti, Alessandra Gentile, Valeria Pecce, Francesca Rosignolo, Anna Rita Virzì, Melissa Milan, Paolo M Comoglio, Eric Londin, Paolo Fortina, Agnese Barnabei, Marialuisa Appetecchia, Ferdinando Marandino, Diego Russo, Sebastiano Filetti, Cosimo Durante, Antonella Verrienti

Research output: Contribution to journalArticlepeer-review

Abstract

Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild-type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto-oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET-negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co-driven by a MET mutation has potential management implications, since the tyrosine-kinase inhibitor cabozantinib-approved for treating advanced MTCs-is a specific MET inhibitor.

Original languageEnglish
Pages (from-to)371-377
Number of pages7
JournalHuman Mutation
Volume39
Issue number3
DOIs
Publication statusPublished - Mar 2018

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